Neuronal Mechanisms of Placebo Effects

Placebo responses are complex and work through several neurobiological mechanisms. The neurotransmitters implicated thus far are dopamine (DA), gamma-aminobutyric acid (GABA), cholecystokinin (CCK), opioids, serotonin, and endocannabinoids. Both conscious expectations and unconscious conditioning can bring about molecular changes using the above neurotransmitters along the distributed biological systems, subserving cognition, emotions, pain control, reward, and learning. Expectations can enhance DA secretion in the reward circuitry of the brain, which has a nucleus accumbens at its epicenter. The prefrontal cortex (PFC), which controls attention and emotional memories, negotiates the path to the reward. The nucleus accumbens (NAc), after capturing the sole attention of the PFC, is able to modulate arousal, emotional tone, and autonomic tone to make the brain seek reward of therapeutic benefit, even when no active treatment is offered. Both DA and endogenous opioids play a key role in modulation of placebo responsiveness. The negative expectations of the person regarding treatment or negative suggestions given by the treater can amplify anxiety and pain by activating several brain regions, such as the anterior cingulate cortex (ACC), PFC, and the insula. Thus, anticipatory anxiety generated acts on two independent pathways: the hypothalamic pituitary adrenal (HPA) axis and the CCKergic pro-nociceptive system. By acting on anxiety, benzodiazepines can block both pathways and reduce pain. But CCK antagonists such as proglumide can only prevent nocebo hyperalgesia, and have no effect on HPA hyperactivity. The ebb and the flow of opioid/CCKergic systems produce the opposing effects of placebo/nocebo. The activation/deactivation between endogenous opioids/DA in NAc helps us understand both placebo and nocebo responses. There are parallels between the placebo response and classical conditioning. Endocrine, immune, and autonomic responses can be conditioned by placebos. Both the expectancy and conditioning mechanisms mediate placebo responses contingent upon previous experiences and social observational learning.